Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis

Abstract

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…As a result, the activated oncogenic network stimulates the initiation and development of TME by multiple reactions. ( , protein-protein interaction previously reported; the thickness of the blue line is qualitatively proportional to the reliability of the data) cancer-metabolism-related genes, oncogenes, and HIF1A triggers genesis of the TME [13,[47][48][49][50].…”

“…The anaerobic metabolism generates lactic acid and results in an acidic TME [46]. Lactic acidosis and an acidic environment in the tumor tissue result in over-expression of various genes, including glycine decarboxylase (GLDC) [13], glucose transporters, SIRT1, COX2, GAC, PDHK1, PFK1, ANT2, and HIF1A. However, acidic environment may cause genetic instability and activation of oncogenes, resulting in expression of hypoxia-induced factor-A (HIF1A).…”

“…The metabolic enzyme glycine decarboxylase (GLDC) is an oncogenic protein that induces generation of cancer stem cells and tumorigenesis of non-small cell lung cancer [13]. This protein causes an increase in glycolysis and the metabolism of glycine, serine, and pyrimidine, promoting stem cell proliferation in several types of cancers.…”

“…However, stromal cells with genetic and epigenetic abnormalities primarily induce the generation of CSCs and the development of malignant tumors [13]. Targeted deletion of Dicer1, the "landscape-modifying" miRNAprocessing endonuclease in osteoprogenitor cells, causes a myelodysplastic syndrome (MDS) in knockout mice, and the Dicer1-deleted mice develop acute myelogenous leukemia [13,92]. These abnormalities are dependent on the type of stromal cells in the microenvironment, because MDS was not observed when Dicer1 was deleted from mature osteoblasts.…”

“…In addition, aggressive tumor cells (such as cancer stem cells) are important in the initiation and development of a malignant TME by active participation in tumor neovascularization and generation of a cancer stem cell niche [9][10][11]. Although stromal cells are considered a promoter during the genesis of the TME [12], dysfunction of stromal cells may induce generation of cancer stem cells and malignant tumors [13]. Rapid progress in the study of the TME has changed the approach to cancer research.…”